tbuckley/cabot-search huggingface dataset:
Survival and Prognostic Factors in Brain Metastases from Breast Cancer Treated with Stereotactic Radiotherapy
Authors: Adam Mitchell, Kieran Palmer, Amanda Fitzpatrick, Alex Bartram, Louise Rockall, Rachel Lewis, Nick Plowman, Hannah Lowe, Glenda Scandura, Pratistha Panday
Journal: Neuro-Oncology (2022)

Abstract AIMS Intracranial metastases are common in patients with breast cancer. Stereotactic radiotherapy (SRT) can improve overall survival (OS) in selected patients; however there is uncertainty over the presence of prognostic indicators in this cohort. Here, we aim to determine whether the number of brain metastases, receptor status and presence of extracranial disease affected OS. METHOD Retrospective analysis was performed for all patients receiving SRT for brain metastases from breast cancer between 2014-2020 at Barts Cancer Centre. Overall survival (OS) was calculated using the Kaplan-Meier method. Differences between groups were assessed using the Log-rank (Mantel-cox) test. RESULTS 109 patients with a histopathologically confirmed diagnosis of breast cancer were included. The median age at treatment was 52 years (IQR:46-60). Of 103 patients with documented receptor status, 22 patients were ER+/HER2+, 32 ER+/HER2-, 20 ER-/HER2+ and 29 triple-negative. 68/105 patients had extra-cranial metastatic disease at treatment with SRT. A median of 2 lesions were treated per patient (range:1-15). Median OS for all patients was 67.4 weeks. Median OS was 91.4 weeks for ER+/HER2+ patients, 64.9 weeks for ER+/HER- patients, 71.4 weeks for ER-/HER2+ and 37 weeks for ER-/HER2- (p=0.001). Median OS was 55.1 weeks for patients with extra-cranial metastatic disease and 91.4 weeks in those without (p=0.017). Median OS was 72.1 weeks in patients with 1-2 brain metastases and 53.7 in those with extensive (3+) brain metastases, however this was not statistically significant (p=0.892). CONCLUSION A trend towards worse OS in patients with triple-negative receptor status and extra-cranial metastatic disease at treatment with SRT warrants further investigation.
Effects of Glycogen Synthase Kinase-3β (GSK3β) Inhibition in Glioblastoma Using Novel Compounds
Authors: Klaudia Rzepecka, Clare Lawrence, Dima Moualla, Joseph Hayes, Jane Alder
Journal: Neuro-Oncology (2022)

Abstract AIMS GSK3β is a constitutively conserved serine/threonine kinase involved in a number of biological processes including cell cycle progression, apoptosis, cellular metabolism, proliferation and differentiation. High expression levels in the brain make this kinase a potential target for treatment of neurological disorders. The aim was to investigate the anti-proliferative and cytotoxic effects of four novel highly selective, type-II GSK3β inhibitors identified by in silico analysis of naturally occurring compounds. METHOD We demonstrate the effects on the cell viability of immortalised cell lines (grade 4 glioblastoma U87MG, foetal astrocytes SVGp12) and short-term glioblastoma patient derived cultures (PD301 and PD304). The compounds were incubated with cells for 24, 48 and 72h and then assayed for cell viability using MTS. The concentration of inhibitors was determined from previous IC50 experiments on purified GSK3β enzyme. The changes in activity status of GSK3β pre- and post-treatment were also determined using immunohistochemistry or Western Blotting. RESULTS Two of the compounds caused significant decrease in cell viability at 24h and 3uM as shown by decrease in viability of 20.5% relative to control. This decrease was larger in the glioma cell lines relative to the glial non-cancerous control (13%). Western blot analysis revealed that activating phosphorylation sites were detectable. More work is needed to determine if this is the mechanism by which reduction in cell viability occurs. CONCLUSION Two of the selected novel compounds have demonstrated ability to decrease glioblastoma cell viability. Future studies will include analysis of the compounds in relation to the BBB-glioma in vitro model.
ChemoSeed®: A Novel Implantable Device for the Treatment of High Grade Gliomas
Authors: Dina Abdelnabi, Colin Watts, Shawn Hingtgen, Alain Valdivia, Christopher McConville
Journal: Neuro-Oncology (2022)

Abstract AIMS The treatment of high grade gliomas (HGGs) is extremely toxic, while offering a dismal prognosis of 15 months survival. Irinotecan (IRN) is a second-line therapy due to its dose-limiting toxicities when delivered systemically. The aim of this research is to formulate IRN into ChemoSeed for local administration to the resection margin of HGGs and evaluate it for toxicity and efficacy in a Patient-Derived Xenograft mouse resection model. METHOD 30 and 40% w/w IRN-loaded ChemoSeeds were manufactured using hot melt extrusion and were subsequently implanted into the resection cavity of HGG tumour bearing mice. RESULTS The 30% w/w IRN-loaded ChemoSeeds showed moderate local toxicity two days after implantation, which diminished by day 4. The 40% w/w IRN-loaded ChemoSeeds showed signs of moderate local toxicity up to six days post implantation, diminishing by day 8 with mild toxicity returning at day 14. Histopathology of the implantation site showed signs of the onset of necrosis at day 45 and 14 for the 30% and 40% w/w IRN-loaded ChemoSeeds. Hematological analysis and clinical chemistry showed no signs of serious systemic toxicity for either the 30 or 40% w/w IRN-loaded ChemoSeeds. The 30% w/w IRN-loaded ChemoSeeds had an 80% survival at day 148, with no sign of tumour recurrence, while the 40% w/w group showed signs of tumour recurrence at day 21, with all mice dead by day 70. CONCLUSION This study demonstrates that the 30% w/w IRN-loaded ChemoSeeds are a promising novel treatment for HGGs that could be quickly translated into the clinic.
Deep Learning for Tumour Segmentation with Missing Data
Authors: James Ruﬄe, Samia Mohinta, Robert Gray, Harpreet Hyare, Parashkev Nachev
Journal: Neuro-Oncology (2022)

Abstract AIMS Brain tumour segmentation remains a challenging task, complicated by the marked heterogeneity of imaging appearances and their distribution across multiple modalities: FLAIR, T1-weighted, T2-weighted, and contrast-enhanced T1-weighted sequences (T1CE). But the use of all four imaging sequences is not always possible. The causes for this are legion, with common examples including corruption by image artefacts and acquisition constraints, such as those imposed in pre-operative stealth studies. We therefore aimed to quantify how well tumour segmentation models perform with incomplete imaging data. METHOD We developed a collection of 30 state-of-the-art deep learning tumour segmentation models, nnU-Net-derived, and deployed them across all possible combinations of imaging modalities, trained, and tested with five-fold cross-validation on the 2021 BraTS-RSNA glioma population of 1251 patients, with additional out-of-sample comparison to neuroradiologist hand-labelled lesions from our own centre. RESULTS Regardless of imaging available, models largely performed well. The best models with varying degrees of missingness were as follows: single sequence available - FLAIR (Dice 0.938); two sequences available - FLAIR + T1CE (Dice 0.943) and three sequences available – FLAIR + T1CE + T2 (Dice 0.945). In comparison, a model with complete data (FLAIR + T1 + T1CE + T2) achieved a similar Dice coefficient of 0.945. CONCLUSION Tumour segmentation models with missing sequences – common in clinical practice - still delineate lesions well, often with comparable performance to when all data is available. This provides opportunity for quantitative imaging in patients and clinical situations wherein full MRI acquisitions are not possible.
The Outcomes Measured and Reported in Meningioma Clinical Effectiveness Trials Are Heterogeneous and Preclude Comparative Analysis of Results: A Systematic Review
Authors: Christopher Millward, Abdurrahman Islim, Sumirat Keshwara, Nisaharan Srikandarajah, Andrew Brodbelt, Anthony Marson, Paula Williamson, Michael Jenkinson
Journal: Neuro-Oncology (2022)

Abstract AIMS Meningioma clinical trials have assessed interventions including surgery, radiotherapy, and pharmacotherapy, but heterogeneity of outcome measurement and reporting often precludes comparative analysis of trial results. This systematic review aimed to summarise the outcomes measured and reported in such trials. METHOD Systematic literature and trial registry searches were performed to identify published and ongoing intracranial meningioma clinical effectiveness trials. Reported outcomes were extracted verbatim, along with an associated definition and method of measurement if provided. Deduplication, grouping, and classification of verbatim outcomes was performed to identify unique outcomes reported in the literature. RESULTS Thirty published articles and 18 ongoing studies were included, describing 47 unique studies: phase II n=33, phase III n=14. Common interventions included: surgery n=13, radiotherapy n=8, and pharmacotherapy n=20. 660 verbatim outcomes were reported, of which 85 were defined. Following deduplication, 416 unique verbatim outcomes remained and were grouped into 119 unique ‘non-verbatim’ outcomes. Those reported most frequently included: blood loss n=15, need for blood transfusion n=12, radiographic response to treatment n=19, eye toxicity after radiotherapy, gastrointestinal toxicity from pharmacotherapy n=40, haematological toxicity from pharmacotherapy n=31, metabolic and nutrition toxicity from pharmacotherapy n=42, progression-free survival n=46, and overall survival n=37. CONCLUSION Outcome measurement and reporting across meningioma clinical trials is heterogeneous and may preclude comparative analysis of trial results. The unique outcomes identified from this systematic literature review will be prioritised through an eDelphi survey and consensus meeting of key stakeholders (including patients), in order to develop a Core Outcome Set (COS) for use in future meningioma clinical trials.
Palliative Carboplatin Chemotherapy in Previously Treated High-Grade Glioma: Real-World Efficacy and Safety
Authors: Meetakshi Gupta, Paul Mulholland, Elena Wilson, Naomi Fersht, Michael Kosmin
Journal: Neuro-Oncology (2022)

Abstract AIMS Effective third-line chemotherapy options for patients after temozolomide (TMZ) and nitrosourea-based chemotherapy for high-grade glioma (HGG) are not well defined. The use of carboplatin is limited due to uncertainly around its effectiveness and tolerability. METHOD Patients with HGG treated with single-agent carboplatin chemotherapy between 2005-2021 were identified from our institutional database. Patient and treatment-related details were acquired from electronic hospital records. SPSS Statistics for Windows, (Version 23.0, IBM Corp.) was used for data analysis. RESULTS A total of 16 HGG patients were identified. This included 9 glioblastoma (GBM) and 3 anaplastic astrocytomas (AA). These 12 patients were used for further analysis. The median age was 48 (22-73) years. All patients initially received a flat dose of 450 mg intravenous carboplatin every 3-4 weeks. All had previously received high dose RT (54-60 Gy), and temozolomide and lomustine-based chemotherapy. Carboplatin was used as 3rd or 4th line treatment. The median number of cycles given was 3 (range: 1-12). Five had rapid decline in performance status after 1-3 cycles. Five patients required dose/ cycle length adjustment due to grade 1 or 2 haematological toxicity. Other than cumulative fatigue, no other &amp;gt;/= grade 2 toxicities were reported. None required inpatient management for treatment toxicities. Median progression-free survival on carboplatin was 3 months (range 1-11 months) and overall survival was 8 months (range 1–26 months). CONCLUSION Carboplatin is a viable treatment option for HGG with acceptable toxicity rates. However, careful patient selection remains key to attaining maximum benefit.
Gliocova: Predictors of Post-Operative Complications, 30 Day Mortality and Readmission After First Surgical Intervention in Brain Tumour Patients in England Between 2013-2018
Authors: Radvile Mauricaite, Kerlann Le Calvez, Andrew Brodbelt, Alex Bottle, Jonathan Gregory, Thomas Booth, Matt Williams
Journal: Neuro-Oncology (2022)

Abstract AIMS The Gliocova dataset uses linked English national cancer data on all 51,775 adult primary brain tumour patients diagnosed between 2013-2018. Here we investigate patient safety and post-operative complications after first surgical intervention. METHOD We identified patients undergoing first surgical intervention (surgical debulking or biopsy) and used a modified Delphi approach to identify diagnosis codes indicating potential post-surgical complications. We calculated Elixhauer Comorbidity Index (ECI) weights based on our data and developed regression models to link patient characteristics and ECI with 30-day mortality, readmission and chance of complication. RESULTS 29,258 out of 51,775 patients underwent a surgical intervention (28,173 surgical debulking; and 1,207 biopsy). 11,959 (40.9\%) patients had at least one comorbidity during first intervention admission. In hospital mortality was 0.99\% (N = 289), 30-day mortality was 2.3\% (N = 677) and 30-day readmission was 12.7\% (N = 3,725). 13,137 patients (44.9\%) had at least one complication code from our defined list, either during their first surgical intervention or during a 30-day readmission. Predictors of 30-day mortality, readmission, and risk of complications included age, ECI score, number of complications, type of intervention (biopsy vs surgical debulking), income quintile, and tumour type (i.e., Glioblastoma versus other types of brain tumours). CONCLUSION To our knowledge this is the first study in England to assess post-surgical complications in a large brain tumour patient cohort. Our further work will focus on variation in outcomes between different centres/ centre volumes/ regions and the cost of complications. More information: https://blogs.imperial.ac.uk/gliocova/about-gliocova/.
Survival Outcomes of Stereotactic Radiotherapy for Ten or More Brain Metastases
Authors: Hamoun Rozati, Matt Williams
Journal: Neuro-Oncology (2022)

Abstract AIMS Discrepancies exist in the use of stereotactic radiotherapy (SRT) for patients with 10 or more brain metastases. Concerns include multiple metastases being associated with poor survival and the lack of prospective data. We analysed survival outcomes of these patients in a multi-centre cohort. METHOD We performed a retrospective cohort study of 511 consecutive patients from three SRT centres treated for brain metastases between January 2010 - August 2021, censored in January 2022. We assessed survival post-SRT of patients with ≥10 metastases against a matched group of 5-9 and 1-4 metastases using the logrank test for statistical testing. We used a multivariate Cox model to assess the relationship between overall survival and: number of metastases; total volume; primary malignancy; use of systemic anti-cancer therapies with intracranial penetrance; controlled extracranial disease. Results with p-values &amp;lt;0.05 were considered significant. RESULTS Survival data was available for all patients, and for 85-100% of factors in multivariate analysis. 63 patients had ≥10 metastases (median 19). Median survival was 13.3 months, compared with 15.1 and 19.0 months for the 5-9 and 1-4 metastasis groups respectively. Differences were not statistically significant (p-value 0.14). Increasing volume of disease (HR 1.05 [1.01-1.09], p-value: 0.01), non-small cell lung cancer (HR 3.5 [1.35-9.09] p-value: 0.01) and use of systemic anti-cancer therapy with intracranial penetrance (HR 0.239 [0.105-0.547] p-value: &amp;lt;0.01) had a statistically significant effect on survival in multivariate analysis. CONCLUSION Carefully selected patients with multiple metastases have acceptable survival outcomes following SRT and this approach should be more widely considered.
Outcome of Image-Guided Surgical Biopsy of Brain Lesions: A Single Centre Experience
Authors: Ahmed Mohammed Nabil Saleh ElGhamry, Natalie Simon, Mohamed Eltayeb, Surash Surash
Journal: Neuro-Oncology (2022)

Abstract AIMS The aim of this study was to quantify the accuracy of surgical biopsy for brain lesions using different image-guidance techniques, in our tertiary neurosurgical centre. METHOD Retrospective data was collected from electronic and paper patient notes. Data collected included: age, sex, comorbidities, pre-operative functional images, surgeon grade, biopsy method, number of targets, number of samples, result from frozen section and fixed sample histopathology, complications, and length of stay. Methods of biopsy included: ultrasound-guided, frame-based biopsy and frameless Brainlab guided biopsy (free-hand, Varioguide and registration tool -guided). RESULTS A percentage of 11.5% of cases (total = 52) were US-guided biopsy. Navigated frameless biopsies comprised 76.9% of all cases. In these cases, 42.3% of cases were guided by the registration tool, 23% used a fixed “Varioguide” instrument alignment tool and 11.5% were completed using the free-hand method. Overall accuracy of biopsy for all cases was 82.69%. Accuracy rates of different frameless methods were: 81.8% for Brainlab registration- guided biopsy, 66.7% for Brainlab Varioguide biopsy and 100% for Brainlab free-hand frameless biopsies. The percentage of complications was 5.8%. CONCLUSION In our centre, the accuracy of image-guided surgical biopsy for brain lesions was as high as 82.69% with a low complication rate of 5.8%. The Brain lab free-hand technique had the highest diagnostic yield and safety amongst all frameless stereotactic techniques.
Neurosurgery Database for Brain Tumour Patients
Authors: Paolo Jose De Luna, Edward McKintosh, Glenda Scandura, Molly Hilling, Arnab Ghosh
Journal: Neuro-Oncology (2022)

Abstract AIMS We develop an electronic database system for brain tumour patients. This aims to provide accessible and comprehensive data in a unified database for all neuro-oncology patients at Barts Health NHS Trust. METHOD The database was created using Microsoft Access with data categorised using forms and tables. Initially, patients were added retrospectively using the neuropathology list and the neuro-oncology multi-disciplinary team patient lists. Once creation and validation was complete, patients were added prospectively. Queries on neuro-oncology patients can be launched to produce datasets which can be copied to Microsoft Excel spreadsheets for sorting, calculation, and graph creation. RESULTS At the time of writing, records of 1171 neuro-oncology patients who were accepted for MDT discussion at Barts Health NHS Trust are included in the database. It is used to routinely run data queries more efficiently and complete in a shorter time. Queries include post-operative complications, overall survival, histological diagnosis, and average surgery waiting time. These queries have already been used to publish audit-based research papers and will be used increasingly as part of routine clinical governance. CONCLUSION The database yields data about treatment of our brain tumour patients with increased completeness and significant reduction in time to return queries, compared to using standard data management. The database has been used to produce data, including tumour types, seizure incidence, and post-operative complications. We have been successful in producing published research, although low absolute complication numbers in the current dataset have not yet allowed comparison of complications rates at individual clinician and team level.
Modulation of GABA Neurotransmitter Signalling Impacts Glioblastoma Spheroid Growth and Response to Standard Treatment
Authors: Rhiannon Barrow, James A Poulter, Martina A Finetti, Erica Wilson, Colin A Johnson, Lucy Stead
Journal: Neuro-Oncology (2022)

Abstract AIMS We have identified two subtypes within glioblastoma (GBM), defined by whether a specific subset of genes is upregulated (Up responders) or downregulated (Down responders) in response the standard treatment. The biology of therapy-driven transcriptional reprogramming in the two subtypes suggests the differential involvement of GABA neurotransmitter signalling in the underlying treatment resistance mechanisms. Our aim was to address our hypothesis that modulating GABA signalling will impact treatment response in GBM, in different ways for different responder subtypes. METHOD We identified two cell lines representing the different responder subtypes: established GBM cell line A172 is an Up responder; GBM63 is a patient derived Down responder. We have grown these cells as spheroids and inspected the response to standard treatment (2 Gy radiation and 30 mM temozolomide), via growth and cell viability assays, versus untreated controls in the presence and absence of a GABAA receptor (GABAAR) modulators. We have performed RNAseq to investigate the pathways affected by inhibition and treatment. RESULTS In all cases, modulation of GABAAR activity significantly alters both growth and response to standard treatment. However, this is most commonly in different directions in the Up vs Down responders. Furthermore, the majority of genes that are differentially expressed through treatment and inhibition are dysregulated in different directions. CONCLUSION Modulation of GABA neurotransmitter signalling impacts GBM spheroid growth and response to standard treatment. Identifying the key pathways affected in different responder subtypes may indicate how this can be used in the development of more effective combination treatments for GBM.
Where Do People With Primary Malignant Brain Tumours Die? A National Cohort Study in England, Using GlioCova Data
Authors: Micah Caldano, Joanne Droney, Radvile Mauricaite, Kerlann Le Calvez, Matt Williams
Journal: Neuro-Oncology (2022)

Abstract AIMS The Gliocova dataset uses linked English national cancer data on all 51,775 adult primary brain tumour patients diagnosed between 2013-2018. Despite poor outcomes, there is little work on end of life care in primary brain tumour patients. The majority of patients with cancer prefer to die at home, but most do not. METHOD We identified all patients with a malignant primary brain tumour diagnosed in England between 2013-2018 and who died up until 1st of August 2020. RESULTS 20,684 patients were selected. The median age at diagnosis was 68 years (IQR=19), 42% were female. 55% died within 6 months of diagnosis. 36% of people died at home (compared to 24% of the entire population in England), 25% died in hospital, 15% died in a hospice, 9% died in a nursing home. 15% had an unrecorded or other place of death. 47% (n=9,682) patients had radiotherapy, of which 8.7% (n=1,806) had radiotherapy in the 3 months before death; 29% (n=5,947) patients received chemotherapy (6%(n=1,292) during the last 3 months). 87%(n=18,013) patients had surgery (36%(n=7,370) during the last three months). For all treatments the chance of patients dying at home decreases if the patient has treatment in the last three months of life. CONCLUSION To our knowledge, this is the first work exploring the relationship between anti-cancer treatment near the end of life and the location of death. Further work will focus on building a comprehensive model to predict rates of death in hospital, and examine variation on a national level.